N-Nosyl oxaziridines as terminal oxidants in copper(II)-catalyzed olefin oxyaminations

Article abstract of DOI:10.1016/j.tetlet.2010.08.015

We report that N-4-nosyl-3-phenyloxaziridine is an effective terminal oxidant for copper(II)-catalyzed oxyamination recently developed in our labs. This oxaziridine can be prepared on multi-gram scale and is easily purified by recrystallization. The products of oxyamination using this oxaziridine bear protecting groups that can be readily removed in high yields under mild conditions.

Full text of DOI:10.1016/j.tetlet.2010.08.015

Tetrahedron Letters 51 (2010) 5223–5225
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Tetrahedron Letters
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N-Nosyl oxaziridines as terminal oxidants in copper(II)-catalyzed olefin
oxyaminations
*
Sandra M. DePorter, Ashley C. Jacobsen, Katherine M. Partridge, Kevin S. Williamson, Tehshik P. Yoon
Department of Chemistry, University of Wisconsin, 1101 University Avenue, Madsion, WI 53706, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We report that N-4-nosyl-3-phenyloxaziridine is an effective terminal oxidant for copper(II)-catalyzed
oxyamination recently developed in our labs. This oxaziridine can be prepared on multi-gram scale
and is easily purified by recrystallization. The products of oxyamination using this oxaziridine bear pro-
tecting groups that can be readily removed in high yields under mild conditions.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 1 July 2010
Revised 27 July 2010
Accepted 2 August 2010
Available online 11 August 2010
Keywords:
Oxaziridines
Oxyamination
Copper
Amino alcohols
A great variety of natural products, bioactive small molecules,
and chiral reagents for synthesis feature vicinal aminoalcohols as
an important structural element.1 Among the most straightforward
methods for the construction of this substitution pattern is the
Sharpless aminohydroxylation, which utilizes an osmium catalyst
to effect the vicinal difunctionalization of simple alkenes.2 Over
the past several years, there has been increasing interest in the
development of complementary, osmium-free methods to effect
the same transformation.3
Our group has been developing a novel copper(II)-catalyzed ole-
fin oxyamination reaction that uses N-sulfonyl oxaziridines as the
terminal oxidant.4 We originally reported oxyaminations utilizing
N-benzenesulfonyl 3-phenyloxaziridine 15 (i.e., Davis’ oxaziridine).
The oxyaminated products resulting from this transformation (2,
Eq. 1) bear N-benzenesulfonyl groups that require relatively harsh
reducing conditions for their removal. More recently, we reported
conditions that would enable N-4-nosyl-3,3-dimethyloxaziridine 3
to be utilized as the terminal oxidant.6 This oxaziridine produces
oxyamination products bearing a more easily cleaved protecting
group on nitrogen; however, given the sensitivity of the intermedi-
ate imine, the synthesis of 3 is relatively technically demanding
and gives somewhat moderate yields (Fig. 1).7
became interested in exploring the reactivity of N-tertbutylsulfonyl
3-phenyloxaziridine and N-p-nosyl 3-phenyloxaziridine
(Fig. 2). We expected that the oxyamination products arising from
reactions using these oxaziridines would bear N-protecting groups
that have been reported to be removable under acid-catalyzed8
and nucleophilic9 conditions, respectively.
5
6
At the outset of this study, the syntheses of 5 and 6 had previ-
ously been reported by García Ruano et al.10 First, we used this
method to prepare 5 and then assessed its utility in the oxyamin-
ation. Reactions using 5 proved to be considerably slower than the
corresponding reactions using the less sterically demanding oxaz-
iridine 1. Using 10 mol % Cu(TFA)2, we were able to react indene
with 5 and isolate 78% yield of the desired oxyamination product
7 after 6 h (Scheme 1). Unfortunately, deprotection of the product
to afford the free amino alcohol proved to be problematic. When 7
was subjected to a variety of acidic conditions, the benzylidene
aminal could be easily removed, but the N-t-butylsulfonyl moiety
remained intact. Attempts using forcing conditions led only to
unproductive decomposition.
Thus, we next turned our attention to oxyaminations using
N-nosyl oxaziridine 6. However, García Ruano had reported that
the yield of 6 using his protocol was rather modest (57%), and
we were unable to improve the yield further upon extensive opti-
mization. Thus, we performed a straightforward modification of
the procedure reported by Davis5 for preparation of 1 (Scheme
2). Lewis acid-catalyzed condensation of 4-nitrobenzenesulfona-
mide with benzaldehyde affords a crystalline imine intermediate,
which can be oxidized by treatment with aqueous Oxone.11 This
two-step procedure is high-yielding, reliable, operationally facile,
and easily performed on multi-gram scale without purification of
Thus, we wondered whether we could perform copper(II)-cata-
lyzed oxyamination reactions using oxaziridines that: (1) bear
easily removable N-sulfonyl protecting groups than the benzene-
sulfonyl group of oxaziridine 1 and (2) are synthesized using
simpler and higher-yielding protocols than oxaziridine 3. We thus
* Corresponding author. Tel.: +1 608 262 2268; fax: +1 608 265 4534.
E-mail address: tyoon@chem.wisc.edu (T.P. Yoon).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.015

5224
Ref 4
S. M. DePorter et al. / Tetrahedron Letters 51 (2010) 5223–5225
We probed the copper(II)-catalyzed oxyaminations of a variety
of styrenes using oxaziridine 6 as the terminal oxidant; the results
of these experiments are summarized in Table 1. In general, we
found that the reactions using 6 provided slightly lower yields than
the corresponding oxyamination reactions using 1 or 3 under iden-
tical conditions. Nevertheless, we found that the tolerance of sub-
stitution on the styrene substrate to be essentially the same.
In contrast to the N-t-butylsulfonyl group, we found that re-
moval of the 4-nosyl group proceeded easily under the nucleo-
philic conditions reported by Fukuyama and coworkers. Our
optimized process for the oxyamination–deprotection sequence
is outlined in Scheme 3. First, styrene was subjected to oxyamina-
tion in the presence of 6, 5 mol % CuCl2, and 5 mol % Bu4N+ClÀ, and
the benzylidene aminal of the crude product was cleaved in good
yield upon acid hydrolysis. Next, the sulfonyl group was removed
using PhSH and K2CO3. This deprotection procedure is high
yielding and is milder and operationally more convenient than
the strong reducing conditions required for the removal of the
PhO2S
Ph
Ph
2 mol% Cu(TFA)2
10 mol% HMPA
SO2Ph
O
O
N
N
N
+
+
(1)
(2)
Ph
O
Ph
H
CH2Cl2, r.t.
1
3
2
4
Ref 6:
Me
O
Ns
Ph
5 mol% CuCl2
Ns
6 mol% Bu4N+Cl–
Me
N
Ph
Me
Me
CH2Cl2, r.t.
Synthesis of oxaziridine 3 (from Ref 6)
NO2
O
AcOH
S
S
N
Cl
S
CH2Cl2
0 °C to reflux
O2N
O2N
moisture-sensitive
Ns
OH
Me
Table 1
Oxyaminations of styrenes using 6a
Ns
N
Oxone
Me
O
N
5 mol% CuCl2
Ns
Ph
Ns
5 mol% Bu4N+Cl–
Et3N; Et2O
0 °C to rt
K2CO3
H2O/toluene
0 °C
Me
Me
O
N
Me
Me
N
+
Ar
O
CH2Cl2, r.t.
Ph
H
Ar
prone to
hydrolysis
and enamine
formation
3
6
50% yield
(3 steps)
Entry
1
Styrene
Product
Ns
Time
3 h
Yield (%)
Ph
Figure 1. Synthesis of oxaziridine 3.
N
.
O
75
52
Ns
H
Bus
Ns
N
O
N
O
N
Ph
.
2
3
45 min
O
Ph
H
Ph
H
H
6
5
Ns
Ns
Ns
Ph
N
Figure 2. 3-Phenyloxaziridines with varied N-sulfonyl groups. Bus = t-BuSO2;
Ns = 4-NO2PhSO2.
O
3 h
54
Cl
Cl
Ph
Bus
N
O
N
Bus
O
NHBus
4
5
6
7
8
1 h
70
75
65
84
59
Ph
10% Cu(TFA)2
10% HMPA
H
N
Me
Me
Ph
H
TfOH
5
O
OH
Me
Me
CH2Cl2
H2O
+
Ph
CH2Cl2
H
N
8, 27% yield
no Bus cleavage
7, 63% yield
O
3 h
Scheme 1.
Ns
Ph
N
O
2.5 h
1 h
NO2
Me
PhCHO
TiCl4
Oxone
K2CO3
Ns
N
Ns
Me
Ns
O
N
Ph
ClCH2CH2Cl
H2O, toluene
Me
Ph
H
Ph
H
N
6
SO2NH2
25 g
O
27.0 g
72% over
2 steps
Me
Ns
Ph
N
Scheme 2.
O
1.5 h
Ac
Ac
the intermediate. The oxaziridine is a crystalline air- and moisture-
stable solid, samples of which we have been able to store in a
refrigerator for months without noticeable decomposition.
Conditions: 1 equiv of styrene, 1.5 equiv of 6, 5 mol % CuCl2, 5 mol % Bu4N+ClÀ,
CH2Cl2 (0.2 M in styrene), ambient temperature.
a

S. M. DePorter et al. / Tetrahedron Letters 51 (2010) 5223–5225
5225
Ns
References and notes
O
N
1. 5% CuCl2
5% Bu4N+Cl–
CH2Cl2, r.t.
NHNs
NH2
1. Bergmeier, S. C. Tetrahedron 2000, 56, 2561–2571.
Ph
Ph
H
PhSH, K2CO3
MeCN, 50 °C
2. For reviews of the scope of the Sharpless asymmetric aminohydroxylation and
its use in synthesis, see: (a) O’Brien, P. Angew. Chem., Int. Ed. 1999, 38, 326–329;
(b) Nilov, D.; Reiser, O. Adv. Synth. Catal. 2002, 344, 1169–1173; (c) Bodkin, J. A.;
McLeod, M. D. J. Chem. Soc., Perkin Trans. 1 2002, 2733–2746.
OH
OH
6
+
Ph
Ph
2. TFA, 80 °C
H2O:dioxane
9, 70% yield
(2 steps)
10, 81% yield
3. (a) Noack, M.; Göttlich, R. Chem. Commun. 2002, 536–537; (b) Chikkanna, D.; Han,
H. Synlett 2004, 2311–2314; (c) Mahoney, J. M.; Smith, C. R.; Johnston, J. N. J. Am.
Chem. Soc. 2005, 127, 1354–1355; (d) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am.
Chem. Soc. 2005, 127, 7690–7691; (e) Szolcsányi, P.; Gracza, T. Chem. Commun.
2005, 3948–3950; (f) Correa, A.; Tellitu, I.; Domínguez, E.; SanMartin, R. J. Org.
Chem. 2006, 71, 8316–8319;(g)Liu, G.;Stahl, S. S.J.Am.Chem. Soc. 2006, 128, 7179–
7181; (h) Schultz, M. J.; Sigman, M. S. J. Am. Chem. Soc. 2006, 128, 1460–1461; (i)
Desai, L.V.;Sanford, M.S.Angew.Chem.,Int.Ed. 2007,46, 5737–5740;(j)Cochran,B.
M.; Michael, F. E. Org. Lett. 2008, 10, 5039–5042; (k) Beaumont, S.; Pons, V.;
Retailleau,P.;Dodd,R.H.;Dauban,P.Angew.Chem.,Int.Ed. 2010, 49, 1634–1637;(l)
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26; (b) Davis, F. A.; Lamendola, J.; Nadir, U.; Kluger, E. W.; Sedergran, T. C.;
Panunto, T. W.; Billmers, R.; Jenkins, R.; Turchi, I. J.; Watson, W. H.; Chen, J. S.;
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J. Chem. Soc., Chem. Commun. 1988, 931–932.
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Scheme 3.
N-benzenesulfonyl group. The amino alcohol product could be eas-
ily isolated in analytically pure form by standard chromatography
techniques.
Thus, we have discovered that oxaziridine 5 is a useful alternate
terminal oxidant for copper(II)-catalyzed oxyamination of olefins.
It is easily synthesized on multi-gram scale in high yield, purified
by recrystallization, and stored for long periods at low tempera-
ture. Oxyamination reactions using 5 produce aminal products that
can be easily deprotected under mild conditions to reveal the free
amino alcohol. This protocol should therefore serve as a useful
alternative to the methods we have previously reported.
Acknowledgments
The financial support for this research was provided by the NIH
(R01-GM084022), the NSF (CHE-0645447), and the University of
Wisconsin.